PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer

Patrizia Carpinelli, Roberta Ceruti, Maria Laura Giorgini, Paolo Cappella, Laura Gianellini, Valter Croci, Anna Degrassi, Gemma Texido, Maurizio Rocchetti, Paola Vianello, Luisa Rusconi, Paola Storici, Paola Zugnoni, Claudio Arrigoni, Chiara Soncini, Cristina Alli, Veronica Patton, Aurelio Marsiglio, Dario Ballinari, Enrico PesentiDaniele Fancelli, Jürgen Moll

Research output: Contribution to journalArticlepeer-review


PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and crossreactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser10 is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.

Original languageEnglish
Pages (from-to)3158-3168
Number of pages11
JournalMolecular Cancer Therapeutics
Issue number12
Publication statusPublished - Dec 1 2007

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology


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